Nadine Martinet

University of Nice Sophia Antipolis | UNS · Chemistry

Dual-emissive deoxyadenosine analogs were engineered by compiling 7-deaza-7-ethynyl-2′-deoxyadenosine with two-color dyes, 3-HydroxyChromones (3HC), while electronically conjugating the N9-donor of the nucleobase with the 3HC carbonyl. Their spectroscopic properties were investigated in a set of solvents of different polarities. Several improvement...

Glucocorticoid receptor (GCR) transactivation reporter gene assays were used as an initial high-throughput screening on a diversi-fied library of 1200 compounds for their evaluation as GCR antagonists. A class of imidazo[2,1-b]benzothiazole and imidazo[2,1-b]benzoimidazole derivatives were identified for their ability to modulate GCR transactivatio...

Background: Epithelial ovarian cancer has a poor prognosis, mostly due to its late diagnosis and to the development of drug resistance after a first platinum-based regimen. The presence of a specific population of "cancer stem cells" could be responsible of the relapse of the tumor, and of the development of resistance to therapy. For this reason,...

La méthylation de l’ADN est une des marques épigénétiques majeures qui intervient dans la régulation de processus physiologiques importants comme l’empreinte génomique parentale et l’expression tissu-spécifique des gènes. Par ailleurs, la méthylation de l’ADN a été reconnue comme un élément pathologique majeur conduisant au cancer. Les marques épig...

isolation, structure elucidation, and antitumor activity of sesquiterpenes, such as bisabolanes, cadinanes, and the new tricyclic carbon skeleton of compound (III)

In recent years, the role of HDAC6 in neurodegeneration has been partially elucidated, which led some authors to propose HDAC6 inhibitors as a therapeutic strategy to treat neurodegenerative diseases. In an effort to develop a selective HDAC6 inhibitor which can cross the blood brain barrier (BBB), a modified hydroxamate derivative (compound 3) was...

Histone H3 methylation on K9 and/or K27 depends on histone lysine methyltransferases (KMTs). EZH2, one of the components of the PRC2 complex, catalyzes the trimethylation of histone H3K27, which is associated with transcriptional repression and tumor development. H3K9me3 mediated gene silencing may result from other KDMs such as G9a/GLP, SUV39H1-2,...

Twenty one sesquiterpenes were isolated from the organic extract of the Caribbean gorgonian Pseudopterogogia rigida. Among them, seven bisabolanes (1, 2, 9-11, 13 and 14), six cadinanes (15-20) and one sesquiterpene featuring a new tricyclic carbon skeleton (21) are new natural products, while two (6 and 7) are reported for the first time from a na...

Glioblastoma (GBM), a malignant brain tumor, is one of the most aggressive human neoplasms due to its molecular heterogeneity, diffusive growth and multiple mechanisms of resistance to chemotherapeutics. Frequent dysfunctions of tumor suppressors and oncogenes, which lead to overactivation of prosurvival and antiapoptotic signals, are driven by gen...

Introduction: Acute Myeloid Leukaemia is the commonest leukaemia of adulthood carrying a dismal prognosis, with the exception of acute promyelocytic leukaemia which responds to All-Trans Retinoic Acid, ATRA. The aim was to cause HL-60 acute myeloid leukaemia cells which did not respond adequately to ATRA to terminally differentiate using a nucleosi...

Conditions for the metathesis of alkenes in the convergent synthesis of HDAC inhibitors have been improved by continuous catalyst flow injection in the reaction media. Intermediate and target compounds obtained were tested for their ability to induce HDAC inhibition and tubulin acetylation, revealing the key role of the tert-butyloxycarbonyl (BOC)...

The development of modern technologies casts a new light on the natural products as an invaluable source of lead compounds that could guide drug discovery. Cancer stem cells are a subpopulation of cancer cells with a high clonogenic capacity and the ability to reform the parental tumours upon transplantation. They have been proposed to drive tumori...

Les marques épigénétiques non codées dans la séquence de l’ADN sont impliquées aussi bien dans le développement normal que pathologique des êtres vivants parce qu’elles modulent l’expression génique. Transmissibles à la descendance mais réversibles, elles ont généré un immense intérêt thérapeutique et des traitements épigénétiques sont déjà prescri...

Summary DNA and histone methylation are becoming more and more important to understand the regulation of gene expression. Their detection and measures are leaving the research domain to enter the clinical practice. We describe here the main methods which are used to date excluding sequencing and arrays.

Two synthetic approaches to boehmeriasin A are described. A gram scale racemic preparation is accompanied by an efficient preparation of both the pure enantiomers using the conformationally stable 2-piperidin-2-yl acetaldehyde as starting material. The anti-proliferative activity in three cancer cell lines (CEM, HeLa and L1210) and two endothelial...

An innovative synthesis of psammaplin-like structure is proposed based on original methodologies using superacid, microwaves, and S-ene chemistry. The new compounds were evaluated as histone deacetylase inhibitors. The results highlight important considerations when using disulfide prodrugs activated under reductive/oxidative conditions that must b...

In this study, a total of 22 flavonoids were tested for their HDAC inhibitory activity using fluorimetric and BRET-based assays. Four aurones were found to be active in both assays and showed IC50 values below 20 μM in the enzymatic assay. Molecular modelling revealed that the presence of hydroxyl groups was responsible for good compound orientatio...

Epigenetic marks are enzymatic tags deposited on the genome which do not change the DNA sequence but changes gene expression. They are reversible and epigenetic dietary interventions are thus suggested for the prevention of ageing, ageing related diseases and for breaking the vicious circle of the trans-generational epigenetic inheritance of the me...

DNA methylation and histone modifications are important epigenetic modifications associated with gene (dys)regulation. The epigenetic modifications are balanced by epigenetic enzymes, so-called writers and erasers, such as DNA (de)methylases and histone (de)acetylases. Aberrant epigenetic alterations have been associated with various diseases, incl...

Understanding the links between genetic, epigenetic and non-genetic factors throughout the lifespan and across generations and their role in disease susceptibility and disease progression offer entirely new avenues and solutions to major problems in our society. To overcome the numerous challenges, we have come up with nine major conclusions to set...

Post-translational modification of histones is fundamental to the regulation of basic nuclear processes and subsequent cellular events, including differentiation. In this study, we analyzed acetylated forms of histones H2A, H2B, and H4 during induced differentiation in mouse (mESCs) and human (hESCs) embryonic stem cells and during induced enterocy...

Inhibitors of epigenetic targets have entered clinical trials with some success, in particular for combined therapies. Like many other chemotherapeutics these new classes of molecules have dose-limiting toxicities and highly active metabolism in vivo resulting in lower efficacy than expected. This review presents drug delivery strategies proposed t...

Fruits and vegetables are known to possess chemopreventive activities in the fight against cancer. Some active metabolites have been fully characterized and were found to have epigenetic bioactivities such as inhibition of DNA methylation. Among them, polyphenols have demonstrated potent DNA methyltransferase (DNMT) activity. This activity is assoc...

This paper reports the synthesis of a series of evodiamine derivatives. We assayed the ability to inhibit cell growth on three human tumour cell lines (H460, MCF-7 and HepG2) and we evaluated the capacity to interfere with the catalytic activity of topoisomerase I both by the relaxation assay and the occurrence of the cleavable complex. Moreover, w...

Aim: The optimal balance between histone acetylation and deacetylation is important for proper gene function. Therefore, we addressed how inhibitors of histone-modifying enzymes can modulate nuclear events, including replication, transcription, splicing and DNA repair. Materials & methods: Changes in cell signaling pathways upon treatment with h...

Recent research has been carried out on environmentally sensitive fluorescent probes of the 3-hydroxychromone (3-HC) family and their use in the study of DNA methylation. This should allow for a better understanding of the DNA methylation mechanism with respect to the UHRF1/DNMT1 (DNA Methyltransferase 1) tandem, which plays a key role during DNA r...

Retinoid receptors (RRs) play a key role in cell proliferation and differentiation. We characterized the expression of RA receptors and retinoid X receptors (RARs and RXRs) in a series of 111 thyroid tumors and investigated the mechanisms responsible for their deregulation: hypermethylation of the RARB2 promoter, loss of heterozygosity (LOH) in the...

Methylation catalyzed by the DNAmethyltransferases affects the C5 position of cytosine residues in DNA. This physiological process is active from the embryo conception, throughout all its developmental steps, and also later for the maintenance of the adult organism. Excess methylated cytosine in tumor suppressor genes is a consistent hallmark of hu...

As opposed to genetics, dealing with gene expressions by direct DNA sequence modifications, the term epigenetics applies to all the external influences that target the chromatin structure of cells with impact on gene expression unrelated to the sequence coding of DNA itself. In normal cells, epigenetics modulates gene expression through all develop...

Unselected lung cancer patients seem unable to gain in terms of survival from treatment with epidermal growth factor receptor (EGFR) inhibitors. Screening for specific molecular targets involves detection of EGFR1 mutations. The aim of our study was to develop a simple set of tests to detect mutations at the tyrosine kinase domain of the EGFR1 gene...

Characterization of the SOX2-squamous signature. A. Venn diagram representing the overlap between the SOX2 squamous signature and the SOX2 targets in human ESCs. Gene numbers are indicated in the corresponding section. The p-value indicates the significance of overlap (hypergeometric distribution). B. Significantly Enriched Gene Ontology Biological...

The 50 most over-expressed genes in lung SCC versus normal comparison (dataset 1). Gene Symbol, Gene description, Ratio (log2 value) lung SCC/normal. (0.04 MB XLS)

Supplementary genelists xls file, several sheets. (0.42 MB XLS)

Additional Materials and Methods information. (0.09 MB PDF)

GSEA-based enrichment analyses of lung SCC dataset-2. A. Enrichments of human ESC-like molecular phenotypes among the genes deregulated in lung SCC dataset-2. The human ESC consensus gene module (FDR <10-2; left panel) and the human ESC-like gene module (FDR <10-2, right panel) are significantly enriched among the genes over-expressed in lung SCCs....

Effects of SOX2 over-expression in BEAS-2B cells on anchorage-independent growth. A. Colony number quantification. SOX2 over-expression leads to a significant increase in BEAS-2B colony number. Of note, these colonies become are largely visible macroscopically upon SOX2 over-expression. B. Colony size quantification. SOX2 over-expression leads to a...

Array-CGH analyses of lung and uterine cervix SCCs. A. Whole genome array-CGH profiles for lung tumors #15 (left panel) and 35 (right panel). For both tumors, the 3q26.33 amplification (green arrow) represents the highest copy number increase detected over the entire genome. Chromosome numbers are indicated above the graph, and the different chromo...

Western blot analysis of SOX2 expression in transduced lung squamous cell lines. BEAS-2B, NCI-H226, and Calu-1 cells were transduced with a SOX2 lentiviral vector (or control). For each cell line, protein extracts were submitted to western blot analysis after normalization of protein loading. Endogenous SOX2 is visible as a thin band in the three c...

SOX2 immunostainings individual results for 51 lung SCC. Individual nuclear and cytoplasmic staining scores obtained for the 51 primary tumors. The 5 tumours found with high level amplifications in the initial arrayCGH screen of 26 tumours are indicated in bold. (0.04 MB XLS)

Union of the SOX2-squamous and the lung SCC signatures. Union of the SOX2-squamous and either of the lung SCC signatures (142 genes in total). Expression ratios (log2 values) are indicated. (0.04 MB XLS)

Known SOX2 target genes significantly correlated to SOX2 expression in human lung SCC. Union of the 71 SOX2 activated target genes significantly correlated to SOX2 expression and the 26 SOX2 repressed genes significantly anti-correlated to its expression in lung SCC (97 genes in total). (0.04 MB XLS)

Squamous cell carcinoma (SCC) of the lung is a frequent and aggressive cancer type. Gene amplifications, a known activating mechanism of oncogenes, target the 3q26-qter region as one of the most frequently gained/amplified genomic sites in SCC of various types. Here, we used array comparative genomic hybridization to delineate the consensus region...

Recent studies have shown that embryonic stem cell-like molecular phenotypes are commonly activated in human epithelial primary tumors and are linked to adverse patient prognosis.(1,2) However it remains unclear whether these correlations to outcome are linked to the differentiation status of the human primary tumors(1) or represent molecular remin...

qRT-PCR primers and Taqman probes sequences.

Rest-RG© analysis. For each RR, the x-fold relative expression ratios (R) were computed by Rest-RG©, based on 2-log of absolute gene regulation, with their associated Standard Errors (SE). Ratios in the selected sample (CHBE, BEAS-2B, H1648, H2087, H2342, A549, H69, H513, skin and SMC) are normalized to reference genes and corresponding NHBE contro...

Recapitulation of raw qRT-PCR data computed for lung tumor samples. n: number of cDNA dilutions replicates amplified for each sample, mTOP: mean of the n Take-Off Point values computed by the Rotorgene software, mAE: mean of the n Amplification Efficiencies computed by the Rotorgene software, SD: Standard Deviation, R2: coefficient of correlation,...

Bestkeeper® analysis of lung tumor samples data. For each gene, the number of samples analyzed (N), the Geometric (GM) and Arithmetic Means (AM) of all the mTOP values, the maximum (Max) and minimum (Min) mTOP values are indicated with their Standard Deviations (SD [± mTOP]) and Coefficients of Variation (CV [%mTOP]). Significant SD [± mTOP] values...

Recapitulation of raw qRT-PCR data. n: number of cDNA dilutions replicates amplified for each sample, mTOP: mean of the n Take-Off Point values computed by the Rotorgene software, mAE: mean of the n Amplification Efficiencies computed by the Rotorgene software, SD: Standard Deviation, R2: coefficient of correlation, Av. mAE: average of all the mAE...

Bestkeeper® analysis. For each gene, the number of samples analyzed (N), the Geometric (GM) and Arithmetic Means (AM) of all the mTOP values, the maximum (Max) and minimum (Min) mTOP values are indicated with their Standard Deviations (SD [± mTOP]) and Coefficients of Variation (CV [%mTOP]). Significant SD [± mTOP] values (> 1) are indicated in bol...

Retinoid Receptors are involved in development and cell homeostasis. Alterations of their expressions have been observed in lung cancer. However, retinoid chemoprevention trials in populations at risk to develop such tumors have failed. Therefore, the pertinence of new clinical trials using second generation retinoid requires prior better understan...

Introduction: We report a survey of mesothelioma survival rates with insights into the survival benefit because of pemetrexed. We also studied a potential link between specific single nucleotide polymorphisms of transcobalamin II (TCII) gene and susceptibility to both asbestos and pernetrexed. Methods: Clinical and occupational data from 287 consec...

We report a survey of mesothelioma survival rates with insights into the survival benefit because of pemetrexed. We also studied a potential link between specific single nucleotide polymorphisms of transcobalamin II (TCII) gene and susceptibility to both asbestos and pemetrexed. Clinical and occupational data from 287 consecutive mesothelioma patie...

Vitamin A is used as a generic term for all vitamin A derivatives with retinol-like biological activity. Retinol is the main parent compound for vitamin A. It derives from carotenoids (provitamin A) and also directly from the pre-formed vitamin A contained in the diet. The term "retinoid" is a generic descriptor of compounds structurally related to...

The energy transfer between two coumarin compounds having donor emission/acceptor absorption spectra overlap was studied firstly in solution by applying an excess of the acceptor. The observed transfer was then confirmed in the bichromophoric compound resulting from the covalent binding of the two fluorophores via a short alkyl chain.

Epigenetic changes, or heritable alterations in gene function that do not affect DNA sequence, are rapidly gaining acceptance as co-conspirators in carcinogenesis. Although DNA methylation signature analysis by methylation-specific polymerase chain reaction has been a breakthrough method in speed and sensitivity for gene methylation studies, severa...

The main objective of this research was to define a structured and functionalized support for future biomedical applications (model of “low-density bioarray”). The experiments were carried out by using stereolithography process with a special SU-8 photoresist and the reproducibility of the method was studied by analyzing the surface profi...

Lung carcinogenesis is a complex process requiring the acquisition of genetic mutations that confer the malignant phenotype as well as epigenetic alterations that may be both manipulated in the course of therapy. Aberrant gene function and transcriptional silencing by CpG island hypermethylation has become a critical component in the initiation and...

Individuals exposed both to cigarette smoke and respiratory pollutants at work incur a greater risk of development of airway hyperresponsiveness (AHR) and accelerated decline in forced expiratory volume in 1 s (FEV1) than that incurred by subjects undergoing each exposure separately. We examined whether smoking cessation or smoking reduction improv...

Due to smoking prevalence and the poor efficiency of current therapy, lung cancer is the leading cause of cancer death in developed countries, and its worldwide incidence is steadily increasing. Gene therapy by direct intratumoral injection of different types of gene constructs through a fiberscope has been suggested and evaluated in a few patients...

The retinoblastoma protein (pRB) is encoded by the RB1 gene whose promoter contains several putative binding sites for ICBP90 (Inverted CCAAT box Binding Protein of 90 kDa), a transcriptional regulator of the topoisomerase IIalpha gene. ICBP90 has two consensus binding sites for pRB in its primary sequence. Here, we show that pRB and ICBP90 co-immu...

In the present study, the level of benzo[a]pyrene 7,8-diol-9,10-epoxide-N(2)-deoxyguanosine (BPDE-N(2)-dG) in normal bronchial epithelial cells from non-cancerous bronchus of 22 lung cancer subjects was evaluated and compared to the lung parenchyma. We found very high formation of BPDE-N(2)-dG adduct in samples corresponding to a pure preparation o...

Transglutaminase type 1 (TGase 1) is a member of a class of enzymes that catalyze the cross-linking of proteins, a characteristic feature of epidermal differentiation and squamous metaplasia. The role of TGase 1 has been extensively studied in epidermis but not in the lung. Using a polyclonal anti-TGase 1 antibody prepared in our laboratory (TGase-...

A prerequisite to the developement of an efficient cell and/or gene therapy for lung cancer is a precise characterization of the inflammatory cell populations spontaneously present in the tumor stroma associated with this cancer. This study was designed to define the cytotoxic potential and the relationship with stroma development of tumor infiltra...

Genetic mechanisms underlying origin and progression of lung cancer are still poorly understood, despite the numerous studies which identified many genomic alterations. Using polymorphic microsatellites, allelic imbalances have been frequently found at loci such as 3p, 5q, 8p, 9p and 9q, 11p and 11q, and 17q without either histologic specificity or...

Recent studies have suggested that nerve growth factor (NGF) may play a role in inflammation and bronchial hyperresponsiveness in asthma. Neither the types of cells that produce NGF in the human airways nor the effect of inflammation on NGF expression are clear. The two-fold aim of the present study was to determine whether airway smooth muscle pro...